A review of the interplay between tuberculosis and mental health

Aims

Tuberculosis and mental illness share common risk factors including homelessness, HIV positive serology, alcohol/substance abuse and migrant status leading to frequent comorbidity. We sought to generate a comprehensive literature review that examines the complex relationship between tuberculosis and mental illness.

Methods

A literature search was conducted in MedLine, Ovid and Psychinfo, with further examination of the references of these articles. In total 316 articles were identified. It was not possible to conduct a formal meta-analysis due to the absence of randomised controlled data.

Results

Rates of mental illness of up to 70% have been identified in tuberculosis patients. Medications used in the treatment of common mental illnesses, such as depression, may have significant interactions with anti-tuberculosis agents, especially isoniazid and increasingly linezolid. Many medications used in the treatment of tuberculosis can have significant adverse psychiatric effects and some medications such as rifampicin may reduce the effective doses of anti-psychotics y their enzyme induction actions. Treatment with agents such as cycloserine has been associated with depression, and there have been reported cases of psychosis with most anti-tuberculous agents. Mental illness and substance abuse may also affect compliance with treatment, with attendant public health concerns.

Conclusions

As a result of the common co-morbidity of mental illness and tuberculosis, it is probable that physicians will encounter previously undiagnosed mental illness among patients with tuberculosis. Similarly, psychiatrists are likely to meet tuberculosis among their patients. It is important that both psychiatrists and physicians are aware of the potential for interactions between the drugs used to treat tuberculosis and psychiatric conditions.     

Functional consequences of mutations in the autophagy genes in the pathogenesis of Crohn's disease

Genome-wide association studies have highlighted a number of genes involved in autophagy, which are of potential importance in the pathogenesis of Crohn's disease (CD). The associated polymorphisms in ATG16L1 and IRGM have been confirmed, and functional studies have begun to shed light on how they link to CD pathogenesis. In this review we consider the most salient aspects of this rapidly expanding field.     

Gastric Bypass Increases Ethanol and Water Consumption in Diet-Induced Obese Rats

Background

Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment for morbid obesity. Increased alcohol abuse after RYGB resulted in recommendations to exclude patients with alcohol abuse histories from RYGB. The purpose of our study was to examine the effects of a RYGB on ethanol intake in diet-induced obese rats (high-fat diet).

Methods

The animals underwent RYGB and were habituated along with their sham-operated obese controls and with lean rats to increasing concentrations of ethanol in a two-bottle choice paradigm.

Results

RYGB rats' daily consumption of ethanol averaged 2?g/kg at 2?% habituation and 3.8?g/kg at 4?% habituation, twice as much as sham-operated obese controls and 50?% more than normal-diet lean controls. Obese controls drank on average 1?g/kg of ethanol (2 and 4?%), significantly less (50?%) than lean controls did. RYGB rats when given higher ethanol concentrations (6 and 8?%) or no ethanol drank significantly more water than lean and obese controls did (66 and 100?%, respectively), and their enhanced total fluid intake was associated with increased food intake, which was significantly higher than in lean (66?% more calories; food + alcohol) and obese controls (44?% more calories). The lower alcohol intake in the obese controls than in the lean rats suggests that obesity may interfere with alcohol's rewarding effects and RYGB may remove this protective effect.

Conclusions

The overall enhancement of consummatory behaviors (both ethanol and water) suggests that RYGB may facilitate alcohol consumption, which in vulnerable individuals could lead to abuse and addiction.     

Reversible pulmonary arterial hypertension associated with interferon-beta treatment for multiple sclerosis

Interferon (IFN) therapy has an important role in the treatment of multiple sclerosis and chronic hepatitis C infection. A few case reports have described an association between IFN therapy and the development of irreversible pulmonary arterial hypertension (PAH), and it is currently listed as a possible drug-induced cause of PAH in the most recent classification of pulmonary hypertension. A causal link between IFN use and PAH remains to be elucidated; many reports of PAH resulting from IFN occur in individuals with some other risk factor for PAH. The authors present a case involving a patient with multiple sclerosis with no known risk factors for PAH, who developed severe PAH after exposure to IFN therapy. The patient experienced significant clinical and hemodynamic improvement, with normalization of her pulmonary pressures after the initiation of combination therapy for PAH. At 28 months after diagnosis, she remains asymptomatic with no hemodynamic evidence of PAH and has been off all PAH therapy for 10 months.     

Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis

We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function. Here, we show using an immunocompetent mouse model of chronic HBV infection that birinapant and other Smac mimetics are able to rapidly reduce serum HBV DNA and serum HBV surface antigen, and they promote the elimination of hepatocytes containing HBV core antigen. The efficacy of Smac mimetics in treating HBV infection is dependent on their chemistry, host CD4⁺ T cells, and TNF. Birinapant enhances the ability of entecavir, an antiviral nucleoside analog, to reduce viral DNA production in HBV-infected animals. These results indicate that birinapant and other Smac mimetics may have efficacy in treating HBV infection and perhaps, other intracellular infections.Studies using animal models indicate that TNF is an important effector cytokine that promotes clearance of hepatitis B virus (HBV) infection (1, 2). Compelling human data show that HBV-infected patients, particularly those with detectable serum HBV surface antigen (HBsAg), are at increased risk of HBV reactivation when treated with TNF antagonists (3, 4). Therefore, therapeutics that augment the mechanisms through which TNF constrains HBV could be of great benefit to patients with chronic HBV infection. Cellular inhibitor of apoptosis proteins (cIAPs) regulate TNF signaling by promoting NF-κB activation downstream of TNF receptor 1 (TNFR1) ligation, and this activation, in turn, promotes cell survival and antagonizes the cell death-inducing potential of TNF (5). When the function of cIAPs is antagonized, TNF-mediated ligation of TNFR1 causes cell death (6–8). Inhibitors of cIAPs promote TNF-mediated death of primary cancer cells in vitro and in xenograft models (9–13). However, there is considerable controversy regarding the effects of Smac mimetics on and the potential deleterious consequences for immunity to infection (14, 15).There are three major mammalian inhibitor of apoptosis proteins (IAPs) called cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP). Mice that are deficient in cIAP1 and cIAP2 in the liver show enhanced and efficient clearance of HBV infection (1). This major finding raises the possibility of targeting IAPs to promote HBV clearance in patients, but several key issues need to be addressed. In this study, we examine these issues, and we specifically investigate if antagonizing IAPs after chronic infection has been established recapitulates the outcomes in cIAP-deficient mice. Small-molecule inhibitors differ in terms of their specific chemical properties, and it would be of interest to know if these differences impact their efficacy in HBV infection. In contrast to conditionally gene-targeted mice, a drug antagonist would interfere with IAP function both intermittently and in tissues beyond the liver. The impact of this and potential collateral consequences, therefore, need to be addressed. It is also critical to establish that the drug candidates have a mechanism of action consistent with the on-target effects predicated through gene-targeting experiments. Our study examines and addresses the issues raised above, and our preclinical data indicate that the cIAP antagonist birinapant and perhaps, other Smac mimetics may have therapeutic efficacy in the treatment of chronic HBV infection.     

Contributions of general internal medicine teaching units

OBJECTIVE: To identify and describe general internal medicine teaching units and their educational activities. DESIGN: A cross-sectional mailed survey of heads of general internal medicine teaching units affiliated with U.S. internal medicine training programs who responded between December 1996 and December 1997. MEASUREMENTS AND MAIN RESULTS: Responses were received from 249 (61%) of 409 eligible programs. Responding and nonresponding programs were similar in terms of university affiliation, geographic region, and size of residency program. Fifty percent of faculty received no funding from teaching units, 37% received full-time (50% or more time), and 13% received part-time (under 50% time) funding from units. Only 23% of faculty were primarily located at universities or medical schools. The majority of faculty were classified as clinicians (15% or less time spent in teaching) or clinician-educators (more than 15% time spent in teaching), and few were clinician-researchers (30% or more time spent in research). Thirty-six percent of faculty were internal medicine subspecialists. All units were involved in training internal medicine residents and medical students, and 21% trained fellows of various types. Half of the units had teaching clinics located in underserved areas, and one fourth had teaching clinics serving more than 50% managed care patients. Heads of teaching units reported that 54% of recent graduating residents chose careers in general internal medicine. CONCLUSIONS: General internal medicine teaching units surveyed contributed substantial faculty effort, much of it unfunded and located off-campus, to training medical students, residents, and fellows. A majority of their graduating residents chose generalist careers. Presented at the national meeting of the Society of General Internal Medicine, April 1998, and the Bureau of Health Professions, June 1998. This work was supported by the Division of Medicine, Bureau of Health Professions, Health Resources and Services Administration, U.S. Department of Health and Human Services, Rockville, Md, grant 103HR960470P000-000; and the Society of General Internal Medicine.     

Improving patient safety culture in general practice: an interview study

Background

When improving patient safety a positive safety culture is key. As little is known about improving patient safety culture in primary care, this study examined whether administering a culture questionnaire with or without a complementary workshop could be used as an intervention for improving safety culture.

Aim

To gain insight into how two interventions affected patient safety culture in everyday practice.

Design and setting

After conducting a randomised control trial of two interventions, this was a qualitative study conducted in 30 general practices to aid interpretation of the previous quantitative findings.

Method

Interviews were conducted at practice locations (n = 27) with 24 GPs and 24 practice nurses. The theory of communities of practice — in particular, its concepts of a domain, a community, and a practice — was used to interpret the findings by examining which elements were or were not present in the participating practices.

Results

Communal awareness of the problem was only raised after getting together and discussing patient safety. The combination of a questionnaire and workshop enhanced the interaction of team members and nourished team feelings. This shared experience also helped them to understand and develop tools and language for daily practice.

Conclusion

In order for patient safety culture to improve, the safety culture questionnaire was more successful when accompanied by a practice workshop. Initial discussion and negotiation of shared goals during the workshop fuelled feelings of coherence and belonging to a community wishing to learn about enhancing patient safety. Team meetings and day-to-day interactions enhanced further liaison and sharing, making patient safety a common and conscious goal.